Spontaneous malignant granulosa cell tumors of the ovary occur in pubertal SWR, certain of the Fl hybrids, and SWR x SJL recombinant inbred (RI) strains. A genetic component is evident in the RI strains where one strain has a 15% incidence, two strains have a 2% incidence, and the remaining strains are free of spontaneous tumors. Endocrine studies show that the host mice have depressed gonadotropin activity, reduced ovarian steroidogenesis, increased serum thyroxine levels, and tumor tissue that lacks LH/hCG receptors. The tumor tissue shows two classes of epidermal growth factor receptors with differing kinetics and significant elevation of receptor numbers above that found in normal ovaries. Recently, we have found that feeding the adrenal steroid dehydroepiandrosterone (DHEA) enhances the incidence of spontaneous tumors and induces these same tumors in some but not all RI strains that were previously free of spontaneous tumors. Each of the endocrine changes reported above represents significant changes in granulosa cell regulatory mechanisms modulated by steroids. Studies are continuing to: (1) determine the number of genes involved and their chromosomal location; (2) characterize tumor cell membranes for receptors for FSH, somatomedin-C, insulin, and other serum borne growth factors; (3) evaluate tumor cells for non-steroidal secretory product(s) that may be suppressing endogenous gonadotropin activity; and (4) determine the active metabolite of DHEA that induces ovarian tumors. (S)